Yang Chang-Huan, Shen Yan-Jhih, Lai Ching Jung, Kou Yu Ru
Institute of Physiology, School of Medicine, National Yang-Ming University Taipei, Taiwan.
Department of Pharmacology and Toxicology, School of Medicine, Tzu Chi University Hualien, Taiwan.
Front Physiol. 2016 Jun 27;7:263. doi: 10.3389/fphys.2016.00263. eCollection 2016.
Obstructive sleep apnea (OSA), manifested by airway exposure to intermittent hypoxia (IH), is associated with excess reactive oxygen species (ROS) production in airways, airway inflammation, and hyperreactive airway diseases. The cause-effect relationship for these events remains unclear. We investigated the inflammatory role of ROS-sensitive AMP-activated protein kinase (AMPK) in IH-induced airway hypersensitivity mediated by lung vagal C fibers (LVCFs) in rats. Conscious rats were exposed to room air (RA) or IH with or without treatment with N-acetyl-L-cysteine (NAC, an antioxidant), Compound C (an AMPK inhibitor), ibuprofen (a cyclooxygenase inhibitor), or their vehicles. Immediately after exposure (24 h), we found that intravenous capsaicin, phenylbiguanide, or α,β-methylene-ATP evoked augmented LVCF-mediated apneic responses and LVCF afferent responses in rats subjected to IH exposure in comparison with those in RA rats. The potentiating effect of IH on LVCF responses decreased at 6 h after and vanished at 12 h after the termination of IH exposure. The potentiating effect of IH on LVCF-mediated apneic and LVCF afferent responses was significantly attenuated by treatment with NAC, compound C, or ibuprofen, but not by their vehicles. Further biochemical analysis revealed that rats exposed to IH displayed increased lung levels of lipid peroxidation (an index of oxidative stress), AMPK phosphorylation (an index of AMPK activation), and prostaglandin E2 (a cyclooxygenase metabolite), compared with those exposed to RA. IH-induced increase in lipid peroxidation was considerably suppressed by treatment with NAC but not by compound C or ibuprofen. IH-induced increase in AMPK phosphorylation was totally abolished by NAC or compound C but not by ibuprofen. IH-induced increase in prostaglandin E2 was considerably prevented by any of these three inhibitor treatments. The vehicles of these inhibitors exerted no significant effect on the three IH-induced responses. These results suggest that 24-h IH exposure sensitizes LVCFs, leading to an exaggerated reflex and afferent responses to chemical stimulants in rats. Moreover, this IH-induced LVCF sensitization is mediated through a cascade of inflammatory responses in the airways involving increases in ROS, AMPK activation, and cyclooxygenase metabolite release.
阻塞性睡眠呼吸暂停（OSA）表现为气道间歇性缺氧（IH），与气道中活性氧（ROS）产生过多、气道炎症及气道高反应性疾病相关。这些事件之间的因果关系仍不清楚。我们研究了ROS敏感的AMP激活蛋白激酶（AMPK）在大鼠肺迷走神经C纤维（LVCF）介导的IH诱导气道高敏反应中的炎症作用。清醒大鼠暴露于室内空气（RA）或IH中，同时给予或不给予N-乙酰半胱氨酸（NAC，一种抗氧化剂）、化合物C（一种AMPK抑制剂）、布洛芬（一种环氧化酶抑制剂）或它们的溶剂处理。暴露后立即（24小时），我们发现与RA大鼠相比，静脉注射辣椒素、苯乙双胍或α,β-亚甲基-ATP可引起接受IH暴露的大鼠中LVCF介导的呼吸暂停反应和LVCF传入反应增强。IH对LVCF反应的增强作用在IH暴露终止后6小时降低，在12小时消失。用NAC、化合物C或布洛芬处理可显著减弱IH对LVCF介导的呼吸暂停和LVCF传入反应的增强作用，但它们的溶剂处理则无此作用。进一步的生化分析显示，与暴露于RA的大鼠相比，暴露于IH的大鼠肺中脂质过氧化水平（氧化应激指标）、AMPK磷酸化水平（AMPK激活指标）和前列腺素E2（一种环氧化酶代谢产物）升高。用NAC处理可显著抑制IH诱导的脂质过氧化增加，但化合物C或布洛芬处理则无此作用。NAC或化合物C可完全消除IH诱导的AMPK磷酸化增加，但布洛芬处理则无此作用。这三种抑制剂中的任何一种处理均可显著阻止IH诱导的前列腺素E2增加。这些抑制剂的溶剂对这三种IH诱导的反应均无显著影响。这些结果表明，24小时的IH暴露使LVCF致敏，导致大鼠对化学刺激的反射和传入反应增强。此外，这种IH诱导的LVCF致敏是通过气道中的一系列炎症反应介导的，包括ROS增加、AMPK激活和环氧化酶代谢产物释放。
